Anti-angiogenic/ Anti-Vasculogenic Therapy for Triple Negative Breast & other Cancers

Rathin Das, Founder and CEO of Synergys Biotherapeutics talked about antibody fusion therapy for cancer treatment at http://www.bio2devicegroup.org event.

Synergys is a preclinical stage biotherapeutics company, developing polyfunctional antibody drugs.  It has established an antibody-linked biological payload system called Antibody-Targeted Anti-vasculogenic Payload (A-TAP). The Company’s most advanced product candidate generated from this system is Anti-EGFR-TAP that is being developed as a new generation anti-angiogenic/anti-vasculogenic biotherapeutic for Triple Negative Breast Cancer (TNBC) and other EGFR+ malignancies.

Angiogenesis is the development of new vasculature from preexisting blood vessels and/or circulating endothelial cells, and is essential for neoplastic proliferation, progression, invasion and metastasis. VEGF (vascular endothelial growth factor), PDGF (Platelet-derived growth factor ), bFGF (basic fibroblast growth factor) are among the most prominent of various growth factors and their signaling pathways that support angiogenesis. Due to the commercial success of the anti-angiogenic antibody drug bevacizumab (Avastin®) by Genentech/Roche, the field of angiogenesis has been generating significant interest as potential target for possible anti-cancer therapy. Bevacizumab is an anti-VEGF MAb which blocks angiogenesis by inhibiting VEGF-A . The MAb interacts nonselectively with its receptors VEGFR1 and VEGFR2.

However, bevacizumab suffers from several safety and efficacy issues, despite its approval for various cancers, including colorectal, renal, cervical carcinoma, glioblastoma, and head and neck and others. It failed to delay the growth of metastatic breast cancers, failed to improve the quality of life of the patients, and its side effects were significant, leading to reversal of the drug’s FDA approval in 2011. Another anti-angiogenic MAb , Ramucirumab (Cyramza) from ImClone, (recently acquired by Eli Lily), targets VEGFR2, and has been recently approved. Ramucirumab has been approved for gastric cancer and NSCLC, but it failed at clinical Phase III for metastatc breast cancer.

Earlier to the development of bevacizumab, Endostatin, a 20 kDa fragment of collagen XVIII, was identified as a naturally occurring inhibitor of endothelial cell proliferation in vitro and angiogenesis in vivo. Although highly efficacious in decreasing tumor burden in animal models, and safe in humans in very high doses, no consistent evidence of antitumor activity for recombinant human endostatin (huEndo) was observed in human trials. Several explanations have been advanced for huEndo’s efficacy failure in humans, including its rapid clearance, low potency and sub-optimal presentation as the monomeric form . Despite these limitations, a proprietary formulation of endostatin (EndoStarÒ) has completed Phase III and IV testing and is now approved in China, providing further evidence of its safety and potential for efficacy, said Das.

Synergys is utilizing an anti-EGFR monoclonal antibody as a targeting domain to facilitate the delivery of a mutant form of human endostatin, huEndo-P125A (where Alanine substitution of Proline 125, significantly increases anti-angiogenic potency of endostatin), as a biological anti-angiogenic payload, for the treatment of cancer. Most importantly, unlike earlier failures of endostatin used as an anti-angiogenic in clinical trials, where monomeric form of endostatin with N-terminal amino acid deletions was used, “ in our approach a ‘dimeric’ fusion of a full-length endostatin-P125A mutant to a targeted antibody is utilized”, said Dr. Das. The “dimeric”endostatin-P125A generated by linking two molecules of endostatin-P125A to two heavy chains of an antibody molecules shows excellent inhibition of endothelial cell angiogenesis and profound inhibition of vasculogenic mimicry or VM. VM is the formation of an alternative tumor vasculature assembled directly from tumor cells and not from vascular endothelial cells.

Synergys is developing Anti-EGFR-TAP for the treatment of Triple-negative breast cancer (TNBC), which is an especially deadly subtype of breast cancer, said Das. It comprises approximately 15% of newly diagnosed breast cancer and is overrepresented in young women, in patients with BRCA1/2 mutations and in women of African ancestry (1). At present, TNBC has the poorest survival outcome of all breast cancer subtypes. TNBC lacks the three most commonly targeted receptors in human breast cancer: the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)/neu. However, the expression of epidermal growth factor receptor 1 (EGFR, HER1) is reported in greater than 60% of TNBC. Although no approved targeted therapy is currently available for the treatment of this highly aggressive subtype of breast cancer, several recent clinical studies involving agents for DNA repair by poly (adenosine disphosphate-ribose) polymerase (PARP inhibitors) have shown promising results in some BRCA1 and BRCA2 mutated TNBC patients. However, the role of PARP inhibitors in unselected TNBC patients is still uncertain and newer more effective targeted therapies are urgently needed for TNBC .

In addition to tumor induced angiogenesis, TNBC readily exhibits VM. Indeed Anti-EGFR-TAP demonstrated excellent inhibition of endothelial cell angiogenesis and profound inhibition of VM of TNBC cells.  Anti-EGFR-TAP treatment also showed significant inhibition of growth of triple negative breast cancer xenografts relative to those treated with cetuximab (Anti-EGFR MAb).  Various published studies have shown that none of the approved angiogenesis inhibitors inhibit VM. Indeed, not all anti-angiogenic antibodies show anti-VM activities. To this end, in a head to head comparison, three other anti-angiogenic antibodies were negative in VM assays relative to Anti-EGFR-TAP. The inhibitory effects of Anti-EGFR-TAP for both angiogenesis and vasculogenic mimicry , therefore, is both interesting as well highly promising as a potential drug for progressive cancers, said Das.  Further Das observed, it is important to inhibit both angiogenesis and VM, not just angiogenesis, to inhibit overall tumor growth.

Synergys is attempting to collect more safety and efficacy data with significant animal studies and also looking at other EGFR+ malignancies . Das said that the A-TAP technology is a new generation of cutting-edge biological payload system that is capable of generating highly efficacious polyfunctional biotherapeutics , with multibillion dollar market potential.  Currently, they are seeking financing for rapid product development. The company is also open to negotiations around partnering and structuring deals around out-licensing business model.

(Edits by Rathin Das).

“The Dog Lived and So Will I” by Teresa J. Rhyne — Book Review

“I was hideous.  Hideous.  In preparing for chemo I’d thought about the hair loss, of course, and concentrated on the fact that it would grow back.  I thought about losing my eyelashes and decided eye shadow and liner would work miracles.  I knew of the bloating weight gain the steroids could cause but told myself that was better than nausea and again it was temporary; after all, Seamus (dog) had gained 20 percent of his body weight and just as quickly was back in fighting shape.  Menopause would come, sure, but it was going to do that sooner or later anyway, and before it happened I was no more aware than anyone else of the true meaning of hot flashes and how you burn from the inside out, so that hadn’t bothered me either.  Somehow I had overlooked skin rashes as a side effect and never, never had I given thought to what these side effects would all be like together.  Not until that moment, face to mirrored face.  …….. How does one recover from this? Impossible. ……. I can’t do this.  I can’t”.

Heaven forbid and if one ever has to go through cancer treatment, having read this book not only would help one navigate the morass of health care system, but also giver clear hope that not only “it too shall pass” but it is worth waiting for the “cookie moment”.

Teresa poured her heart and soul (not to mention her hard earned money) to take her beagle, Seamus, survive through an aggressive form of cancer.  She cried buckets of tears, took him for his biopsy and chemo appointments, rushed him to the hospital when his white blood count dropped dangerously low, and stood up to the neglectful veterinarians, to get him the care he needed.  However, in one of life’s cruel ironies, before long she discovered that she had a lump in her breast and the biopsy showed it to be the one of the most aggressive forms of cancer, a triple negative breast cancer.   How does one survive such traumas?  The answer is “love”.

Some may consider this a story of surviving cancer, but this is a story about the rock, the glue, and the toast.  After being divorced twice, Teresa had a new boyfriend Chris, ten years younger, smart, funny, wise, and infinitely kind.  Little did they know that he would be the rock (the pack leader) on whom she would need to lean during both Seamus’s and her own illness and treatment.  When Teresa is completely dejected and feels she can’t do this anymore, he bakes her cookies at four in the morning, drives her to all her medical appointments, tries out wigs with her, and in solidarity as she looses her hair, he grows his hair, making a deal that he would only cut when she needed a cut, after the regrowth of her hair.

Camry the beagle (Photo credit: laRuth)

Teresa for her part is the glue that holds their family together.  She leans on him but gives him space.  She is infinitely grateful and brings her and Chris’s family into the fold, eventually bringing them to meet each other.  Seamus who loves toast, steals people’s hearts with his cuteness.  He brings much needed joyful respites to their little family.

I cry easily but this book did not make me cry.  I teared up often reading this touching tender story, but I also laughed a lot.  Deep grief is wrapped in smart, witty, humorous, funny anecdotes.  And then there is treasure trove of information about little questions that are hard to get answered.  Is it painful for the radioactive tracer to be injected in order to locate the tumor for a biopsy, how long it takes for a chemo treatment, how long does it take for radiation, and more.

And while majority of the health care personnel and physicians are compassionate, committed, and are deeply dedicated to the welfare of their patients, there are some who are clearly uninterested, detached, and neglectful.  Teresa stands up (unfortunately not always succeeding) for her right as a patient to get timely information and reasonable care.  One of the physicians who rarely sees her patients, leaving actual care in the hands of the nurses, assures Teresa (about her dangerous white blood count crash), these side effects are very common, and the nurses know how to deal with them.  We deal with this stuff all the time.”  Teresa points out, that the nurse did not have the answers on how to deal with them and says, “it’s not common to me.  I don’t deal with it all the time”.  Contrarily, she is enormously grateful and highly appreciative of the compassionate and thorough care she received at the UCLA cancer center and particularly Dr. Amer Karam.

This is an engaging, funny, sweet, uplifting, heartwarming story.  After all, who would not like to read about a cute dog’s hilarious antics?