Founder's Site

James E. Summerton, Ph.D.

Founders-Site.Onco-Tools.com

[2] Feasibility of Curing any cancer by 2020

[ link 2 ]

Feasibility of
Curing any cancer by 2020

( 24 August 2017 )

Our goal is to complete by the year 2020 the development and pilot-scale implementation of a system for curing any cancer without harming the patient.  Three major objectives must be achieved in order to meet that very challenging goal. Below I describe why I believe all three objectives can be completed by 2020. Those three objectives are:

  1. Assemble a master list of cancer-essential transcripts which have been identified by many different cancer researchers studying a wide variety of human cancers.
  2. Prepare and safety test an arsenal of advanced drugs which are effective and specific for blocking those identified cancer-essential transcripts.
  3. Identify a reasonable path for getting personalized cocktails of such advanced drugs to cancer patients in a timely manner and at an affordable price.

1.  Regarding a master list of cancer-essential transcripts, many cancer researchers are currently focused on identifying just such transcripts in human cancers – particularly researchers studying alternatively spliced RNA isoforms and non-coding RNA transcripts whose expression differs between normal and cancer cells.  However, most such researchers are using inadequate tools (siRNAs & shRNAs) for such identifications. Those inadequate tools have poor stability in biological systems, are plagued by multiple off-target effects, and provide only modest sequence specificity, see link [5]. 

To remedy this inadequacy, in August 2017 Onco-Tools, LLC will make available to cancer researchers far better tools (delivery-enhanced Onco-Morpholinos, which are: stable in biological systems; generally free of off-target effects; and, have the highest sequence specificity; see link [5]).  With these superior tools we expect the rate of identification of cancer-essential RNA transcripts will be markedly accelerated and the identifications will be more reliable.

These identifications and testing of cancer-essential transcripts will be further accelerated and made more rigorous by recent advances in RNA sequencing afforded by Pacific Biosciences’ ultra-long-read RNA sequencing system – which avoids the gaps and mis-alignments which have commonly plagued studies of alternatively-spliced isoforms in the past.  Furthermore, advances in xenografting of patient-derived cancers now allow higher grafting success rates and greater rigor for in vivo testing of prospective cancer-targeted drugs (Mol. Cancer Ther. doi:10.1158/1535-7163.MCT-16-0721).  Combined, these recent advances are expected to provide by 2019 an adequate master list of cancer-essential transcripts sufficient to guide the selection of the arsenal of Onco-Morpholinos from which each patient’s custom cocktail will be assembled.

2.  Regarding the arsenal of advanced drugs, each drug in that arsenal must be both effective and selective for blocking its specific cancer-essential transcript in a cancer, and must be safe for normal cells of the patient by virtue of the patient’s normal cells lacking that targeted cancer-essential transcript. 

In our custom cocktail system the core of each drug in the cocktail comprises a Morpholino antisense oligo which is complementary to the specific cancer-essential transcript targeted by that particular drug.  Such Morpholino antisense oligos ( https://en.wikipedia.org/wiki/Morpholino ) have an unmatched combination of properties which makes them by far the best available antisense therapeutics.

Safety and efficacy:  In September of 2016 the US Food and Drug Administration (FDA) approved for clinical use the first Morpholino drug (Eteplirsen) for treatment of Duchenne muscular dystrophy (see:  Lim, et al.  Drug Design, Development and Therapy 11: 533 (2017)).  In addition, Morpholinos are currently being studied as possible therapeutics for dozens of other diseases (see: link [6]).

Broad applications:  Over 100,000 custom-sequence Morpholino oligos have been used by thousands of research scientists around the world for specifically altering the function of selected RNA transcripts of many different organisms – from viruses to humans.  Since the year 2000, research studies utilizing these Morpholinos have been reported in over 8,400 peer-reviewed scientific papers and reviews, and in over a dozen books.  These scientific publications are tabulated at:  pubs.gene-tools.com , and the tabulations to mid-2017 include 470 papers relating to cancers, tabulated at: gene-tools.com/cancerpubs .

Recent advances:  In August of 2017  Onco-Tools, LLC is launching a new class of delivery-enhanced Onco-Morpholinos targeted against 500 different cancer-related RNA transcripts that have been reported in human cancers – see product catalog and on-line store at: Onco-Tools.com

The potency of these delivery-enhanced Onco-Morpholinos can be about 50-fold greater than the potency of conventional Morpholinos available from GENE TOOLS, LLC prior to 2017.  This very substantial potency increase for delivery-enhanced Onco-Morpholinos was achieved through a recent optimization program funded by Onco-Tools, LLC and jointly carried out by Onco-Tools, LLC and GENE TOOLS, LLC.

The initial delivery-enhanced Onco-Morpholinos launched in August of 2017 are formulated for use in cultured cells. Later in 2017 we expect to complete and launch delivery-enhanced Onco-Morpholinos formulated for use in vivo.  Preliminary experimental results suggest that some variation of this new in vivo formulation will provide the long-sought safe and efficient in vivo delivery of non-ionic antisense oligos that is needed for routine and affordable treatment of many different diseases in humans – starting with cancers.

Logistics of designing and producing an arsenal of drugs targeted against an adequate number of cancer-essential transcripts:   I am guessing that cancer researchers carrying out extensive studies in a wide variety of cultured human cancer cells, and in zenografts of patient-derived cancers, will identify two to three thousand RNA transcript isoforms and non-coding transcripts which are present in cancers but absent from normal cells.  Of those few thousand transcripts, I am guessing that only a few hundred will be found (by empirical testing with Morpholino oligos) to be essential for the viability of the cancers – ie., found to be cancer-essential transcripts and so suitable for productive targeting with Onco-Morpholino drugs.  It is those drugs targeting the identified cancer-essential transcripts which will constitute the arsenal of drugs from which each patient’s cocktail of about 4 to 10 drugs will be assembled.

From the prospective of a drug developer who targets cancer-related proteins, timely development of safe and effective drugs targeted against several thousand cancer-related proteins would be an impossible job.  And it would probably remain an impossible job even if every pharmaceutical company in the world joined in the effort, they all shelved their other programs, and the work was carried out around the clock for three years.

In contrast, every month GENE TOOLS, LLC  (which contracts to produce delivery-enhanced Onco-Morpholinos for Onco-Tools, LLC) designs, synthesizes, and ships to scientists worldwide 500 to 1,000 different custom-sequence Morpholinos.  Thus, producing a few thousand extra Onco-Morpholinos over the course of several months will not be an undue burden.  Likewise, producing pilot-scale quantities of a few hundred Onco-Morpholino drugs targeted against selected cancer-essential transcripts is also entirely feasible.

Identifying a reasonable dosing scheme for an n-of-one patient population – a crucial challenge in personalized medicine:  Each patient’s cancer is unique at the molecular level and so the Onco-Morpholino cocktail to treat that unique cancer will likely also be unique.  Thus, at first glance it might appear to be an impossible challenge to select a reasonable dosing scheme for any specific patient’s cancer by means of a conventional dose escalation study.

However, selecting a reasonable dosage and treatment frequency can be achieved by using patient-derived xenografts, which entail growing small chunks of a patient’s cancer in multiple immune-deficient mice.  In such a system the transplanted patient’s cancer in each of the mice is virtually identical to that in all of the other mice with respect to genetic and phenotypic heterogeneity.  Thus, one can do a fairly conventional dose escalation efficacy study by virtue of having essentially converted the original n-of-one patient population to an n-of-many test population.

Results from a number of such dosing studies in mice will inform us as to what are likely reasonable dosing schemes for the many different drugs in our arsenal of a few hundred Onco-Morpholinos.  That information, in turn, will afford reasonable dosage schemes that can be used in the safety studies to be carried out in healthy adults. 

Safety testing of each prospective Onco-Morpholino drug targeted against a specific cancer-essential transcript will be carried out on just a few dozen healthy humans.  These safety studies will be designed to be uniquely safe for the test subjects (mice and ultimately humans) by virtue of having a custom antidote on hand which is capable of rapidly rendering the previously-injected Onco-Morpholino drug inert.  This custom antidote (described in: Journal of Drug Discovery, Development, and Delivery 3(1): id 1020 (2016)) would only be used in the unlikely event that the injected Onco-Morpholino drug caused a severe adverse event in a test subject.

We also plan to make this exceptional precautionary measure available to at least the first few hundred patients treated with custom cocktails of Onco-Morpholinos.  That will entail providing the components for a custom cocktail of antidotes specific for rendering inert every component drug in the patient’s treatment cocktail.  Thus, in the very unlikely event that a patient exhibits a serious adverse effect from their treatment cocktail, those antidote components would be quickly mixed and delivered into that patient – wherein the custom cocktail of antidotes would render inert the previously delivered custom cocktail of drugs.

3.  Getting cures to patients
promptly and affordably

The US congress has tasked the US Food and Drug Admin. (FDA) with assuring that drugs widely used in the US are adequately safe and effective – based on sound scientific evidence.

To achieve that Congressionally-mandated task of confirming both adequate safety and adequate efficacy before approving any new therapy, the FDA typically first requires a safety trial with enough subjects (typically healthy humans) to confirm that the new therapy is adequately safe.

In a subsequent double-blind placebo-controlled efficacy trial on actual patients, some of the patients are treated with the new therapy and others are treated with the placebo (or a current best-practices comparison therapy).

In both the safety trial and the efficacy trial the FDA requires that enough subjects be tested to achieve statistical significance regarding whether or not the new therapy is adequately safe and is adequately effective.  For validity, such trials rely on the bedrock principle of statistical significance.  And until now that has generally been both adequate and appropriate for approval of new therapies.

However, in our custom cocktail system for curing any cancer a specific custom cocktail of Onco-Morpholinos will be specific for selected cancer-essential transcripts identified in a particular patient’s cancer.  Furthermore, that specific cocktail will likely have optimal efficacy only against that particular patient’s specific cancer which that custom cocktail was designed to treat.  Thus, after treating that patient, that particular custom combination of Onco-Morpholinos may never be used again.  This is because there will likely be tens of billions of possible cocktail combinations to choose from – making it relatively improbable that another patient’s cancer would be optimally treated with exactly the same cocktail.

Therefore for such a case as ours wherein one unique cocktail therapy is developed for only a single patient whose cancer likely has a unique combination of cancer-essential transcripts, the conventional FDA requirement for statistically significant clinical trial results are completely stymied.  Stated differently, current FDA clinical trial requirements are completely inappropriate and unworkable for personalized medicine wherein the patient population having a unique disease (unique at the molecular level) comprises only a single individual.

Thus as I see it, the FDA may be facing a very important regulatory challenge by 2020, or soon thereafter.

More specifically, I expect that development of our custom cocktail system for curing any cancer without harming the patient will likely be completed by or soon after 2020. I believe this system will be by far the best way for curing cancers without harming patients, and it may well be the only reliable way to achieve that goal in a timely and affordable manner.  However, it appears that current FDA rules are completely inadequate and unworkable for regulating personalized therapies which are designed for treating a single disease (single at the molecular level) which afflicts just a single patient. I contend that not having suitable regulatory procedures in place when needed (in 2020 ?) would be a huge loss for cancer patients, our healthcare system, our country, and our world.

Happily, the leadership of the FDA has long been aware of the now rapidly approaching wave of personalized therapies.  This is evidenced by formation in 2004 of The Genomics and Targeted Therapy Group in the Center for Drug Evaluation and Research (CDER).  This group is working to prepare the FDA for regulatory challenges the FDA will face with the arrival of personalized therapies (see page 17 of a 61-page paper published in October of 2013 titled: “Paving the Way for Personalized Medicine: FDA’s Role in a New Era of Medical Product Development”).

Further, Dr. Janet Woodcock, head of the FDA’s Center for Drug Evaluation and Research (CDER), is clearly a champion leading the effort to prepare the FDA for developing and adopting regulations suitable for the needs of developers and recipients of personalized therapies.  This is illustrated by excerpts from a speech Dr. Woodcock gave at a luncheon hosted by the Personalized Medicine Coalition in Washington D.C. in 2013.  In that speech she made a number of points relating to personalized therapies:

  • “The FDA will need to turn the clinical trial paradigm on its head in order to allow more specifically targeted personalized drug therapies to get to market faster.”
  • “We are going to have to change the way drugs are developed. Period.”
  • “But in order to develop trials to test these drugs, the FDA and drug developers need a new definition of clinical trials that recognizes therapies will be targeted at subsets of conventionally defined diseases.”
  • “The way trials were developed in the past should not influence or govern the way things are done in the future.”
  • “That path ahead won’t be easy and will require a grand change in the way clinical trials are thought about by drug regulators and developers.  We’re going into uncharted waters here.  I think it’s going to be a big challenge for everyone.”

Plan A:    Based on the above, I have high hopes that the FDA can indeed develop and implement appropriate and practical rules suitable for promptly and affordably regulating personalized therapies.  To that end, in 2018 I plan to propose a meeting with the NCI (National Cancer Institute) and the FDA to jointly devise a demonstration program in Oregon (such as described in link [9]) which will serve as a test bed for new regulations covering production, testing, and use of personalized therapies, with the principal focus being on our custom cocktails for curing all cancers.

Clearly such new rules and regulations must provide scientifically sound assurances of both safety and efficacy, but they must also enable greatly streamlined regulatory approvals which are timely (days, not decades), affordable (hundreds of dollars, not hundreds of millions of dollars), and practical (three pages of paperwork, not tens of thousands of pages).

Also, in the case of a personalized therapy most of the regulatory costs for that unique therapy will necessarily fall directly on a single patient, or on the entity who must pay for that therapy.  Therefore, the new personalized therapy regulations need to strip away conventional rules which incur substantial time and costs – while providing no significant gain with respect to safety and/or efficacy.  In this regard, I believe my 32 years of hands-on experience in devising, developing, producing, testing, and providing Morpholinos to the research community (see link [10]) provides an excellent background from which to guide the development of regulations which rigorously assure safety and efficacy, while also streamlining and minimizing costs of production, processing, structural validation, and biological testing of these Onco-Morpholino-based custom therapies.     

In principle, it would be quite desirable to join forces with the NCI and the FDA to devise and implement a new greatly streamlined regulatory system expressly designed for personalized therapies, where that streamlining contributes to assuring such therapies are both practical and affordable.

Contingency plans :   While in principle a joint effort with the NCI and the FDA would be desirable, in practice there might be insurmountable barriers to joint development of an adequately streamlined regulatory system for personalized therapies.  The concern is that within the FDA there may be great resistance to stripping away current  one-size-fits-all rules, where such rules may be appropriate for conventional drugs that are to be used to treat diseases with large patient populations – but in the context of personalized therapies those same rules may incur untenable costs in time and money, or such rules might simply be impossible or impractical to apply to personalized therapies. 

My concern is that if our cancer cures program is completely at the mercy of the FDA then our custom cures, no matter how safe and effective they are, might never be approved for patients.  If this occurred, it most likely would be due to certain persons within the FDA insisting on applying regulatory requirements that raise costs in time and money to such a level that our cures are rendered impractical or unaffordable, or those persons insisting on applying regulatory requirements which no personalized therapy could ever meet because a clinical trial with a sample size of one patient inherently can never reach statistical significance.  Most likely such insistence on conventional clinical trials would be made on the contention that such trials are essential to assure that the safety and efficacy of our nation’s drug supply must be “protected” by only allowing regulatory approvals on the basis of conventional tried and true statistically significant clinical trial results – in spite of such trials being inherently unsuited for validly assessing safety and efficacy in a clinical trial with an n-of-one sample size.

On the possibility that by 2020 FDA regulations remain in effect which would preclude prompt and affordable regulatory approvals of personalized therapies, even after those therapies have been confirmed by scientifically sound means to be safe and effective, I believe it is prudent to develop contingency plans by which we can provide our custom cocktails to cancer patients – even if FDA regulations remain unsuitable for regulating personalized therapies. 

While there are several strategies which might achieve this goal of getting our custom cocktails to patients in spite of a lack of suitable FDA regulations, probably the simplest and most likely to succeed would entail making and using our custom cocktails outside of the jurisdiction of the FDA.

In this regard, under Article I, Section 8, Clause 3 of the US Constitution the US Congress passed the Federal Food, Drug, and Cosmetic Act (most recently amended in 2016).  That Act mandates that the US Food and Drug Admin. is to ensure that drugs in interstate commerce are adequately safe and effective – based on sound scientific evidence. Therefore in regard to regulating drugs, the FDA only has jurisdiction over drugs which are, or are intended to be, transported across state lines.

Plan B:  If by 2020 the FDA has not yet adopted rules appropriate for prompt and affordable regulatory approvals  of personalized therapies which have been shown by scientifically sound means to be safe and effective, then it will be time to implement a contingency plan for getting our custom cocktails to cancer patients in a prompt and affordable manner.   My preferred Plan B would be to make and use our custom cancer therapies only in Oregon – which would require that cancer patients visit Oregon for their treatments with these products of intra-state commerce.

In this regard, it should be mentioned that the FDA has adopted the position that drugs which are made and used solely within a given state, but which were made from precursors which were shipped across state lines, constitute products of interstate commerce and so are within the FDA’s regulatory jurisdiction.  The FDA has cited 6 US District Court cases which they contend support their claim of regulatory jurisdiction over drugs made and used only within a given state, but which contain one or more components which were shipped from out of state (CPG Sec. 100.200 FDA Jurisdiction Over Products Composed of Interstate Ingredients).  However, a close reading of those 6 court cases (critical analysis by Denis Stearns, partner in Marler Clark law firm) suggests that the FDA is on very thin ice with regard to their claim of such regulatory jurisdiction – particularly if the precursors shipped from out of state were subsequently converted to substances having entirely different molecular structures (ie., no active ingredient of the final drug came from out of state – which will be the case for our custom cocktails).  Therefore, it appears unlikely that the FDA could prevail in claiming jurisdiction over our custom cocktails which would be made in Oregon and used only in Oregon.

Further in regard intra-state drugs whose active ingredients, as well as the final drugs, are made and used only within a given state, I contend that the FDA’s claims of regulatory jurisdiction are unconstitutional.  This is because Amendment 10 of the US Constitution reserves the right to regulate production and use of products of intra-state commerce to the state in which they are made and used, or to persons within that state.  I contend that any attempt by the FDA to usurp those regulatory rights of the state, or persons within the state, is unconstitutional.

Plan C:  On the small chance that the FDA’s claim of jurisdiction over custom cocktails, made and used only in Oregon, were to prevail in court, our next step would be to shift production and use to an agreeable nearby sovereign independent nation (commonly called an Indian reservation).  I suspect that the FDA’s chance would be vanishingly small of prevailing in a claim of regulatory jurisdiction over drugs made and used only in such a sovereign nation.    

 

In closing, personalized therapies are coming soon (2020 ?) and the FDA needs to devise and adopt new rules which provide scientifically sound assessments of safety and efficacy of such therapies, and afford regulatory approvals of safe and effective therapies in a prompt and affordable manner.  Accordingly, I propose that the FDA approve a demonstration program that can serve as a test bed for such new regulations.